title: Pyrrolo-pyrimidones: a novel class of MK2 inhibitors with potent cellular activity.
abstract: Pyrrolo-pyrimidones of the general structure 1 were synthesized and evaluated for their potential as MK2 inhibitors. Potent derivatives were discovered which inhibit MK2 in the nanomolar range and show potent inhibition of cytokine release from LPS-stimulated monocytes. These derivatives were shown to inhibit phosphorylation of hsp27, a downstream target of MK2 and are modestly selective in a panel of 28 kinases.
authors.affiliation: Novartis Institutes for BioMedical Research, global Discovery Chemistry, WSJ-88.508, CH-4002 Basel, Switzerland. achim.schlapbach@novartis.com
authors.forename: Achim
authors.initials: A
authors.lastname: Schlapbach
authors.forename: Roland
authors.initials: R
authors.lastname: Feifel
authors.forename: Stuart
authors.initials: S
authors.lastname: Hawtin
authors.forename: Richard
authors.initials: R
authors.lastname: Heng
authors.forename: Guido
authors.initials: G
authors.lastname: Koch
authors.forename: Henrik
authors.initials: H
authors.lastname: Moebitz
authors.forename: Laszlo
authors.initials: L
authors.lastname: Revesz
authors.forename: Clemens
authors.initials: C
authors.lastname: Scheufler
authors.forename: Juraj
authors.initials: J
authors.lastname: Velcicky
authors.forename: Rudolf
authors.initials: R
authors.lastname: Waelchli
authors.forename: Christine
authors.initials: C
authors.lastname: Huppertz
mesh_terms: D001172:Arthritis, Rheumatoid / Q000188:drug therapy; D020650:Combinatorial Chemistry Techniques; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D055551:HSP27 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology; D015394:Molecular Structure; D009000:Monocytes / Q000187:drug effects; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D016207:Cytokines; D055551:HSP27 Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D017346:Protein Serine-Threonine Kinases; D011744:Pyrimidinones; D011758:Pyrroles; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2